Folic acid, one of the important B vitamins, is a precursor for the biogenetic synthesis of the cofactor, tetrahydrofolic acid conjugate. This later in turn, serves both as a formyl and hydroxymethyl transfer agent in a variety of biological system (B. R. Baker, L. Goodman, R. Koehler, J. Amer. Chem. Soc. 1958, 80, 5779-5786). The analogue 5,8-dideaza-5,6,7,8-tetrahydrofolic acid or the 2-substituted tetrahydro-quinazolinones have attracted considerable attention in chemistry (A. Gangjee, A. Vasudevan, J. Heterocyclic Chem. 1997, 34, 1669-1676; G. Bernath, J. Kobor, J. Lazar, F. Fülöp, J. Heterocyclic Chem. 1996, 33, 1983-1988; G. Bernath, T. Janaky, G. Goendoes, J. Lazar, Z. Ecsery, Pharmazie 1983, 38, 270-271; T. Nishio, M. Fujisawa, Y. Omote, J. Chem. Soc., Perkin Trans. 1, 1987, 2523-2529) and biology (T. Sekiya, H. Hiranuma, M. Uchide, S. Hata, S. Yamada, Chem. Pharma Bull. 1981, 29, 948-954; F. Claudi, G. Giorgioni, L. Scoccia, R. Ciccocuppo, I. Panocka, Eur. J. Med. Chem. 1997, 32, 651-660).

A wide range of biological activities has been discovered for such compounds: anticancer properties, antimicrobial activity against Streptococcus feacium, inhibition of dihydrofolate reductive and thymidilate synthase (M. G. Nair, R. Dhawan, M. Ghazala, T. I. Kalman, R. Ferone, Y. Agumont, R. L. Kisliuk, J. Med. Chem. 1987, 30, 1256-1261), as well as an ability to be a good substrate for partially purified mouse liver folylpolyglutamate synthetase (A. Rosowsky, R. A. Forsch, R. G. Moran, J. Med. Chem. 1989, 32, 709-715). The WO0046214 describes tetrahydroquinazolinones for the treatment of cardiovascular disorders. The WO042025 describes tetrahydroquinazolinones for the treatment and prevention of brain diseases. The WO04034972 describes quinazolinone-like derivatives as kinesin spindle protein modulators.
Although there are some known ways to prepare tetrahydroquinazolinone derivatives (Y. Sanemitsu, S. Kawamura, J. Org. Chem. 1993, 58: 414-418; G. Bernath, F. Fülöp, Synthesis, 1985: 1148-1149), a method starting from the Michael addition of amidine to the highly reactive acrylate analogue, methyl 2-chloro-2-cyclopropylidineacetate, has not previously been reported by other research groups (M. Limbach, S. Dalai, A. de Meijere, Adv. Synth. Catal. 2004, 346: 760-766. For an overview of chemistry of 1 see: A. de Meijere, S. I. Kozhushkov, L. P. Hadjiarapoglou, Topics Curr. Chem. 2000, 207: 149-227). Recently we described a versatile method for the synthesis of cyclobutene annelated pyrimidinones via Michael addition of amidines to compounds of formula I. However, the subsequent thermal cyclobutene ring opening followed by a Diels-Alder reaction led to inseparable mixtures (M. Nötzel, K. Rauch, T. Labahn, A. de Meijere, Org. Lett. 2002, 4, 839-841).
Protein kinases are involved in signaling pathways for such important cellular activities as responses to extracellular signals and cell cycle checkpoints. Inhibition or activation of specific protein kinases provides a means of intervening in these signaling pathways, for example to block the effect of an extracellular signal, to release a cell from cell cycle checkpoint, etc. Defects in the activity of protein kinases are associated with a variety of pathological or clinical conditions, where there is a defect in the signaling mediated by protein kinases. Such conditions include those associated with defects in cell cycle regulation or in response to extracellular signals, e.g., immunological disorders, autoimmune and immunodeficiency diseases; hyperproliferative disorders, which may include psoriasis, arthritis, inflammation, endometriosis, scarring, cancer, etc. Therefore, compounds, which are active in modulating purified kinase proteins, e.g., there is a modulation in the phosphorylation of a specific substrate in the presence of the compound, can be used for the treatment of protein kinase-dependent diseases and conditions, such as cancer, tumour growth, arteriosclerosis, age-related macular degeneration, diabetic retinopathy, inflammatory diseases and the like, in mammals.
Thus, as there remains a need in advantageous therapeutics, a preferred object of the present invention was to provide new pharmaceutically active compounds or compounds for new medicinal indications. A further object of the present invention was to provide a new method for the preparation of tetrahydro- and dihydroquinazolinones.